"Tumor Cell Hypoxia as a Factor in Cancer Therapy" is a long range project aimed at promoting a more quantitative analysis of the effects of therapeutic perturbations on the dynamics of neoplastic growth. Using a variety of in vivo and in vitro assay procedures (spleen colony assay, serial dilution assay, 125I-iododeoxyuridine prelabeling technique, etc.) an attempt will be made to evaluate the importance of the oxygen effect in radiation therapy and to devise therapeutic treatment regimens designed to reduce or eliminate the survival advantage of hypoxic tumor cells. Specifically, the effect of simultaneous administration of hyperthermia and chemical radiosensitizers on the radiation response of oxygenated and hypoxic tumor cells as well as on normal body tissues (bone marrow, skin, intestine) will be investigated. Recent observations in our laboratory indicate that such combination treatments produce pronounced effects on hypoxic tumors: (1) a large fraction of the population is eliminated by selective heat-drug killing of hypoxic tumor cells; (2) the survivors are subject to synergistic radiosensitization. The magnitude of the sensitization effect is such that it becomes easier to eradicate hypoxic tumors than oxygenated tumors. Attempts will be made to further enhance damage to hypoxic cells, while keeping damage to host tissues as low as possible. Based on in vitro studies it appears that reduction in tumor cell pH drastically enhances both heat potentiation of radiation damage and direct heat-induced cell death. We will extend these studies to tumors growing in intact animals. According to the literature it may be possible to induce preferential hyperacidification of tumors in vivo by gassing tumorous animals with 95% air-5% CO2, or by administration of bicarbonate. A different line of work will involve tissue culture studies aimed at evaluating the mechanism of synergistic radiosensitization (damage enhancement vs. repair inhibition) by studying heat-drug effects on the ability of bacteria or mammalian cells to repair damage in preirradiated DNA viruses.